Project Summary HIV infection frequently results in varying degrees of neurocognitive and functional impairment, collectively termed HIV-associated neurocognitive disorders (HAND). Pharmaceutical interventions for HAND have had very limited success. Based on results of large-scale transcriptomic analyses in human samples and in vitro studies of HIV neuropathogenesis, antioxidant inflammation modulators that modify the nrf2/KEAP1 axis may be effective for the prevention and/or treatment of HAND. Our preliminary data show one such compound, Bardoxolone, is effective in reducing HIV replication in human monocytes and macrophages, as well as increasing neuroprotective factors in neurons and macrophages. However, before moving forward with a costly and labor intensive clinical trial, it is important to further characterize the safety and efficacy of Bardoxolone for treating and/or preventing HAND. We propose three studies. First, we will examine the ability of Bardoxolone to mitigate HIV-related cognitive-behavioral deficits in HIV-infected humanized NOG mice. Second, we assess the efficacy of Bardoxolone in reducing viral replication and HIV-induced inflammatory factors in plasma of the humanized mice. Finally, we examine brain tissue of the same humanized mice to determine if Bardoxolone mitigates HIV-induced neural injury and increases expression of neuroprotective factors. Results of these experiments will provide a strong foundation to proceed with an Investigational New Drug application to the FDA and ultimately clinical trials.